The cytotoxic properties and preferential toxicity to tumour cells displayed by some 2,4-bis(benzylidene)-8-methyl-8-azabicyclo[3.2.1] octan-3-ones and 3,5-bis(benzylidene)-1-methyl-4-piperidones

Abstract

This study demonstrated that replacement of the axial protons on the C2 and C6 atoms of various 1-methyl-3,5-bis(benzylidene)-4-piperidones 3 by a dimethylene bridge leading to series 2 lowered cytotoxic potencies. Four compounds 2a and 3a-c emerged as lead molecules based on their toxicity towards different neoplasms and their selective toxicity for malignant rather than normal cells. Some possible reasons for the disparity between the IC 50 values in the two series of compounds are presented based on molecular modeling, log P values and respiration in rat liver mitochondria.

A general HPLC–UV method for the quantitative determination of curcumin analogues containing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore in rat biomatrices

“…Compounds containing the 1,5-diaryl-3-oxo-1,4-pentadienyl group were synthesized at the College of Pharmacy and Nutrition, University of Saskatchewan using reported procedures [2,[6][7][8][9]14]. Tris (tris(hydroxymethyl)aminomethane) and HPLC grade acetonitrile were purchased from Fisher Scientific (Ottawa, ON, Canada).…”

“…1) [4]. The literature refers to this pharmacophore as a curcumin analogue [5], and a substantial number of these compounds have excellent antineoplastic properties [2,[6][7][8][9][10]. Other laboratories are also examining the biological potential of this pharmacophore [5,[11][12][13].…”

Asymmetric synthesis of N-protected 3-methylpiperidin-2-one and its diastereoisomer

“…5-substituted 1-methyl-2-pyridones, which are one kind of piperidone derivative, have been evaluated as active agents against benign prostatic hyperplasia (BPH) and prostate cancer (Hartmann et al, 1994). 3, 5-disubstituted-1-methyl-4-piperidones have selective toxicity towards malignant cells and neoplasms (Pati et al, 2009). Another piperidin-2-one derivative, Sch206272, is a potent NK1/NK2 antagonist, enabling a new approach for treating asthma (Reichard et al 2002).…”

Synthesis of N-Substituted 3,5-Bis(arylidene)-4-piperidones with High Antitumor and Antioxidant Activity

“…The 1,5-diaryl-3-oxo-1,4-pentadienyl groups considered to react at a primary binding site, however the bioactivity will be influenced by others structural units: such as acylating piperidone nitrogen increased cytotoxic potencies and increasing the electron-withdrawing properties of substituents on aromatic ring has advantageous effect on cytotoxicity. [14][15][16][17][18] However, dimethylenbridge between C2-C6 atoms in piperidone was accompanied by reduction of cytotoxic properties exerting a steric impedance to alignment at one or more binding sites as well as variation of hydrophobicity and hence membrane transportation properties. 16 In general the DAP compounds were more effective than curcumin in inhibiting the proliferation of a variety of cancer cell lines.…”

“…[14][15][16][17][18] However, dimethylenbridge between C2-C6 atoms in piperidone was accompanied by reduction of cytotoxic properties exerting a steric impedance to alignment at one or more binding sites as well as variation of hydrophobicity and hence membrane transportation properties. 16 In general the DAP compounds were more effective than curcumin in inhibiting the proliferation of a variety of cancer cell lines. EF24, with ortho-fluorinated phenyl group exhibited anticancer activity in vitro when tested using breast cancer, colon cancer and ovarian epithelial cancer.…”